The main objectives of this project are to: 1) distinguish the metabolic pathways which are responsible for activation and detoxification of the widely occurring carcinogenic polycyclic aromatic hydrocarbons (PAH); 2) to test the validity of the "bay-region" concept of aromatic hydrocarbon carcinogenicity. To achieve these goals we will: 1) perform detailed in vivo and in vitro comparative metabolism studies of PAH carcinogens and their non-carcinogenic analogues; 2) determine the structures, quantities, deposition and elimination of the metabolites; and 3) examine the chemical reactivities of the potentially active metabolite(s) derived from the PAH carcinogen and contrast with those obtained from its noncarcinogenic analogues. Through these studies, we will determine which specific metabolic pathway dictates PAH tumor induction, and how structural parameters influence the metabolism of these compounds and the carcinogenic activities of the resulting metabolites. The information obtained from the proposed project will be useful in establishing structural correlates of carcinogenesis, and hence provide a chemical approach to the risk assessment of other potentially carcinogenic agents. In the proposed experiments, both the in vivo urinary metabolites and in vitro metabolites from microsomal incubation of representative PAH in the benz(a)anthracene (BA) series will be studied. The metabolic profiles will be compared among the analogues which bear methyl or fluorine substituents at various positions of the aromatic skeleton. These compounds are known to exhibit varying degrees of carcinogenicity. The presence of a substituent at different sites of BA skeleton may alter the activation/ detoxification pathways as well as the chemical reactivity of the putative carcinogenic intermediate. Thus, in addition to comparative metabolism studies, the effect of substituents on the reactivity of potentially active metabolites will be examined in terms of their electrophilicity and reaction orientation towards nucleophiles.